multiple memory systems: the power of interactions

Neurobiology of Learning and Memory 82 (2004) 333–346

www.elsevier.com/locate/ynlme

Multiple memory systems: The power of interactions

Robert J. McDonald,a,* Bryan D. Devan,b and Nancy S. Honga

a Department of Psychology and Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge,

AB, Canada T1K 3M4b Behavioral Neuroscience Section, Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging,

NIH, Baltimore, MD, USA

Received 9 March 2004; revised 18 May 2004; accepted 20 May 2004

Available online 15 July 2004

Abstract

Two relatively simple theories of brain function will be used to demonstrate the explanatory power of multiple memory systems

in your brain interacting cooperatively or competitively to directly or indirectly influence cognition and behaviour. The view put

forth in this mini-review is that interactions between memory systems produce normal and abnormal manifestations of behaviour,

and by logical extension, an understanding of these complex interactions holds the key to understanding debilitating brain and

psychiatric disorders.

� 2004 Elsevier Inc. All rights reserved.

Keywords: Interactions; Memory; Hippocampus; Dorsal striatum; Amygdala; Prefrontal cortex; Nucleus accumbens; Anxiety; Depression; Fear;

Obsessive–compulsive disorder; Schizophrenia; Drug addiction; Drug abuse

1. Introduction

Material things are there by means of their images: knowledge is

there of itself; emotions are there in the form of ideas or impres-

sions of some kind, for the memory retains them even while the

mind does not experience them, althoughwhatever is in themem-

ory must also be in the mind. My mind has the freedom of them

all. I can glide from one to the other. I can probe deep into them

and never find the end of them. This is the power ofmemory! This

is the great force of life in living man, mortal though he is!

St. Augustine

This quote, taken from St. Augustine�s book called

‘‘Confessions,’’ is from an entire chapter dedicated to

the topic of memory. The book appears to be St. Au-

gustine�s attempt to understand the complexities of his

own personality. What is interesting about this para-

graph, from our perspective, is that St. Augustine cap-

tures many critical aspects of our memory at a time in

which little or nothing was known about this complexbrain process. This quote suggests that our memory is:

multifaceted and not unitary; the repository for your

* Corresponding author. Fax: +1-403-329-2775.

E-mail address: [email protected] (R.J. McDonald).

1074-7427/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.nlm.2004.05.009

own past and identity; the most important biological

force in the human experience. St. Augustine goes evenfurther and suggests that our memory allows us to

change our behaviour because memory contains a re-

cord of our past history and can be replayed and anal-

ysed, it is the only force through which we can grow and

change as individuals. The latter point is critical for the

current treatise because it is our assertion that the or-

ganization of memory in the mammalian brain and the

neural systems that mediate multiple kinds of memorymust play a pivotal role in our thoughts, emotions,

choices, actions, and even our personalities. Further-

more, these complex neural circuits in our brain not only

contain remnants of our past that are the basis of per-

sonal identity but also exert an enormous influence on

individual behaviour. Quite simply put, this view makes

the bold claim that these brain systems, to a large extent,

determine who we are and how we behave in particularsituations.

The first section of this paper will introduce a simple

but powerful theory about the organization of learning

and memory processes called interactive memory sys-

tems theory (IMST). This theory is similar to the mul-

tiple parallel memory systems (MPMS) theory (White &

mail to: [email protected]

334 R.J. McDonald et al. / Neurobiology of Learning and Memory 82 (2004) 333–346

McDonald, 2002) except the current theory emphasizesinteractions between memory systems. The second sec-

tion will briefly discuss a theory suggesting that normal

and abnormal manifestations of behaviour are deter-

mined, to a large extent, by some complex set of inter-

actions between an individual�s: genetic make-up;

developmental events during pre and post-natal devel-

opment; and accumulated experience through life. The

relationship between the two theories will also be in-troduced and then in the third section we will introduce

an example of how a prenatal developmental event can

alter the balance between two memory systems. In the

last section, we will show evidence that the etiology of

many of the major psychiatric disorders may be linked

to alterations in the integrity of various memory

systems.

1.1. Interactive memory systems theory (IMST): A

precis

The foundation of modern views of the organization

of memory in the mammal was built on the influential

work of Pavlov, Hull, Tolman, and others (Guthrie,

1935; Hull, 1943; Pavlov, 1927; Thorndike, 1932; Tol-

man, 1948). Briefly, each of these scientists formulated ageneral theory of learning and memory in which these

functions were mediated by a basic, underlying mecha-

nism. The proposed mechanisms included classical

conditioning for Pavlov, reinforced stimulus–response

learning in Hull�s theory, and the flexible cognitive

mapping view for Tolman. Despite significant acrimony

between supporters of these different positions, it now

appears that all of these theorists were correct in that themammalian brain uses all of them, as well as other types

of learning mechanisms that appear to be mediated by

different brain circuits.

The first direct evidence for the idea that there were

multiple memory systems in the mammalian brain came

from Scoville and Milner�s (1957) discovery that patientswith damage to the medial temporal lobe showed im-

pairments in some types of learning and memory func-tion but were normal in other aspects. Milner concluded

from this data set that structures in the medial temporal

lobe, most likely the hippocampus, were involved in

complex memory processes, and that brain structures

anatomically and functionally independent of the medial

temporal lobe mediated other learning and memory

function.

Most of the influential multiple memory theories ofmammalian brain function were formulated during the

1970s and were inspired by Milner�s findings. Many of

these theories are dual memory formulations in which

the hippocampus is the central module, while some

other brain area(s), independent of the hippocampus,

mediates non-cognitive S–R habit learning and memory

function (Gaffan, 1974; Hirsh, 1974; O�Keefe & Nadel,

1978; Olton, Becker, & Handelmann, 1979; Tulving,1972).

Hirsh and Krajden (1982) were the first to provide

considerable detail on the different kinds of interactions

that could theoretically occur between cognitive- and

habit-based memory systems. A summary of this view is

captured in the following quote: ‘‘When two different

systems appearing to address the same substantive

matters are present, it is worthwhile to ponder how theymight interact. We think that on some occasions the two

systems compete; on others they cooperate. Once the

fundamental differences between the two systems are

understood, their differing capacities become clear. Each

has capabilities that the other does not. There are cer-

tain features of knowledge that cannot be attained

without using the capacities of both.’’

Thus, in the majority of situations both systems areprocessing information in parallel and it is the circum-

stances or details of a particular situation (e.g., the

performance requirements of a task) that determine

whether systems interact competitively or cooperatively.

While this work was ongoing, a parallel line of re-

search was accumulating a significant body of evidence

suggesting that the dorsal striatum, cerebellum, and the

amygdala were also learning and memory systems (Di-vac, 1968; Kapp, Frysinger, Gallagher, & Haselton,

1979; Schwartzbaum & Donovick, 1968; Thompson &

Krupa, 1994).

The combination of innovative dual memory theories

and evidence of anatomically distinct learning and

memory systems provided a fertile research context in

which various pairs of double dissociations were dem-

onstrated including: hippocampus and cerebellum(Thompson & Krupa, 1994); amygdala and cerebellum

(Hitchcock & Davis, 1986); amygdala and hippocampus

(Kim, Rison, & Fanselow, 1993; Phillips & Ledoux,

1992; Sutherland & McDonald, 1990); hippocampus

and striatum (Packard, Hirsh, & White, 1989) and hip-

pocampus and perirhinal cortex (Gaffan, 1994).

A more recent triple dissociation of learning and

memory function between the hippocampus, amygdala,and dorsal striatum is considered by some to be a wa-

tershed publication for the multiple memory systems

view for several reasons. First, even though various

combinations of double dissociations had already been

shown, this was the first demonstration of a triple dis-

sociation of memory functions in the mammalian brain.

Second, the paper provides the first explicit description

and analysis of both competitive and cooperative in-teractions by using a task analysis method (pp. 17–18).

Finally, the triple dissociation paper and our subsequent

work on interactions between memory systems have

provided a template for future work in this area. This

template includes novel demonstrations of: (1) compet-

itive and cooperative interactions between various

learning and memory systems (McDonald & White,

Fig. 1. According to this view, normal, and abnormal manifestations

of behaviour are determined, to a large extent, by some complex set of

interactions between and individual�s: genetic make-up, pre- and post-

natal developmental events; and accumulated experience through life.

R.J. McDonald et al. / Neurobiology of Learning and Memory 82 (2004) 333–346 335

1993, 1994, 1995a, 1995b; White & McDonald, 1993);(2) memory subsystems within identified learning and

memory systems (Devan, McDonald, & White, 1999;

Featherstone & McDonald, 2004a, 2004b; Ferbinteanu,

Holsinger, & McDonald, 1998; Ferbinteanu & Mc-

Donald, 2000, 2001, 2003); (3) ascending neurotrans-

mitter influences on memory system balance (Kanit et

al., 1998); (4) multiple strategies for solving ‘‘gold

standard’’ learning and memory tasks (Antoniadis &McDonald, 1999, 2000, 2001; Devan & McDonald,

2001; Frankland, Dockstader, & McDonald, 1998;

Frankland, Cestari, Filipkowski, McDonald, & Silva,

1998; McDonald & Hong, 2000); (5) the deleterious ef-

fects of developmental perturbations on the balance

between multiple memory systems (Sutherland, Mc-

Donald, & Savage, 2000); (6) necessary versus incidental

learning and memory processes (McDonald, Foong, &Hong, 2004; McDonald & Hong, 2004; McDonald,

King, & Hong, 2001; McDonald, Ko, & Hong, 2002).

The triple dissociation experiment also inspired a theory

of the organization of learning and memory in the

mammal (White & McDonald, 2002).

This multiple parallel memory systems theory sug-

gests that the mammalian brain has at least three major

learning and memory systems. Each system consists of a‘‘central structure’’ and a set of interconnected neural

structures. The ‘‘central structures’’ of these different

circuits include the hippocampus, amygdala, and dorsal

striatum.

These memory systems acquire information simulta-

neously and in parallel and are always on-line. All of

these systems have access to the same information dur-

ing events but each system is specifically designed torepresent different relationships among the elements of a

learning situation. These elements include stimuli, in-

ternal and external responses, and reinforcers. The

processing style of each system is determined by the

intrinsic organization of the system and the input/output

relations to the rest of the brain. Although they process

information independently the systems can interact co-

operatively or competitively to produce or influenceongoing or future behaviour.

Among the three central memory system structures

the hippocampus is thought to be critical for the for-

mation of episodic memories in which a complex rep-

resentation consisting of the various elements of a

situation or event is constructed (Sutherland & Rudy,

1989; Tulving, 1972). The amygdala has been implicated

in the formation and storage of emotional memories(Bagshaw & Benzies, 1968; Cador, Robbins, & Everitt,

1989; Schwartzbaum, 1964). These emotional memories

uniquely encode the subjective valence of the experience

(positive or negative). The dorsal striatum has been

implicated in stimulus–response habit learning and

memory processes (Packard et al., 1989). This kind of

learning occurs when the subject engages in repetitive

behaviours. For example, the voluntary behaviourselicited while one is driving a car on a repeatedly trav-

elled route by the driver are thought to become under

the control of the habit system.

1.2. Who are you?

The second brain theory that will be explored sug-

gests that normal and abnormal manifestations of be-haviour are determined, to a large extent, by some

complex set of interactions between an individual�s: ge-netic make-up; developmental events during pre and

post-natal time periods; and accumulated experience

throughout the lifespan (see Fig. 1). All of these factors

can have major effects on the organization of the brain.

Alterations in the organization of the brain could affect

overall relationships between each learning and memorysystem (balance in the interactive control of behaviour),

as well as the relationships of these systems with the rest

of the brain. These other neural systems will be ad-

dressed in turn as each is implicated in a specific disor-

der. For the purpose of the present discussion the

combination of factors will be referred to as the GDE

(genes, development, and experience).

Within the normal range of variability, alterations inthe balance between these memory/behavioural systems

can lead to individual personality, affective style, choi-

ces, actions and certain strengths, and weaknesses as-

sociated with different tasks or situations (e.g.,

mathematics, athletics, music, social interactions, etc.).

Fig. 2 shows a hypothetical outcome of complex inter-

actions between GDE factors. One important effect of

these factors is on the organization of various memory/behavioural systems with each other and other neural

Fig. 2. A hypothetical outcome of complex interactions between genes,

development, and experience (GDE) factors. A primary effect of these

interactions is on the organization of various memory/behavioural

systems with each other and with other neural systems. This example

represents a normal individual in which there is a balance between

these systems that when activated result in relatively normal patterns

of behaviour in a wide range of situations.


systems. This example represents a normal individual in

which there is a balance between these systems that

when activated result in relatively normal patterns of

behaviour in a wide range of situations.

A logical extension of this view is that there can also

be changes in the balance of these systems that lead toabnormal manifestations of behaviour including major

psychiatric disorders such as schizophrenia, drug abuse,

and mood disorders. Also, the way memory systems

interact can produce ‘‘abnormal’’ talents, as in the case

of savants and others who display unusual abilities (see

Luria, 1968; Sacks, 1970) that may lead to great ac-

complishments.

In the following section, we will provide an exampleof the influence of a single prenatal developmental event

on the organization of interactive memory systems in

the adult brain. This example was selected because it is

the first factor shown to have an effect on the organi-

zation of interactive memory systems. In contrast, ge-

netic work in this area, to our knowledge, has addressed

learning and memory function in a general manner or

has focused on only one of the identified systems(Kandel, 2002; Yan et al., 2002). Consequently, there

have been no investigations looking at the effects of

genetic manipulations on the interactions and balance

between learning and memory systems. In many cases,

these effects would be subtle, but could have a strong

effect on thoughts and behavioural choices in adulthood.

Similarly, there is a paucity of research directed at un-

derstanding the effects of different types of experience onthe organization of learning and memory systems.

Among the few studies done to date, the effects of ex-

perience has been considered with respect to learning

and memory function in general or on one specific

learning and memory system like the hippocampus(Greenough & Chang, 1989).

1.3. Developmental perturbations: Prenatal exposure to

moderate levels of ethanol on adult cognition

One of the proposals of the present theory is that

developmental events are one of the main factors that

influence the organization of memory systems in themammalian brain. These events can include maternal

stress, diet, and drug use, among others. If these events

occur during critical brain development epochs, the or-

ganization of various brain systems could be perma-

nently altered, affecting adult behaviour. The present

discussion will focus on an animal model of prenatal

exposure to moderate levels of ethanol on adult

cognition.Alcohol-related developmental disorders can be

caused by low to moderate levels of consumption during

pregnancy (Streissguth, Barr, & Sampson, 1990). These

disorders are associated with deficits in high level cog-

nitive abilities without the concomitant morphological

and neurological defects associated with fetal alcohol

syndrome induced by heavy consumption (Jones &

Smith, 1973).Consequently, we developed an animal model to try

and ascertain how moderate prenatal alcohol exposure

may disrupt neurobiological mechanisms of learning

and memory function. The fetal alcohol exposure par-

adigm used in these studies consisted of rat dams re-

ceiving either a 5% ethanol diet, an isocalorically

matched diet, or rat chow. In contrast to other fetal

ethanol paradigms that used high levels of ethanol ex-posure to mimic full blown fetal alcohol syndrome, this

moderate exposure regimen does not affect birth weight,

litter size, neonatal mortality, offspring growth curves or

whole brain weight compared to control groups (Suth-

erland, McDonald, & Savage, 1997).

Despite this apparent normality, neurochemical ob-

servations in the rats exposed to moderate doses of

ethanol during prenatal development noted changes invarious amino acid receptor subtypes and several en-

zymes in the hippocampus (Farr, Montano, Paxton, &

Savage, 1988; Queen, Sanchez, Lopez, Paxton, & Sa-

vage, 1993; Savage, Montano, Otero, & Paxton, 1991).

Interestingly, many of these changes affect mechanisms

essential for normal NMDA-dependent long-term po-

tentiation (LTP). NMDA-dependent LTP is a form of

plasticity found in the hippocampus that has been linkedto learning and memory functions (Davis, Butcher, &

Morris, 1992; Morris, Andersen, Lynch, & Baudry,

1986), it is however, important to note that this is a

controversial and complicated issue that will not be

discussed here. We also found that in adulthood these

rats displayed significant deficits in the induction and

maintenance of LTP at input pathways from the

Fig. 3. The training procedures for the cue-place version of the water

task.


entorhinal cortex to the dentate gyrus of the hippo-campus (Sutherland et al., 1997). These results suggest

that exposure to moderate levels of ethanol during

prenatal development permanently impairs NMDA-de-

pendent plasticity mechanisms. Accordingly, we hy-

pothesized that these neurobiological changes should

also lead to learning and memory deficits on a task

shown to require hippocampal function like the spatial

version of the Morris water task (Morris, Garrud,Rawlins, & O�Keefe, 1982; Sutherland, Kolb, &

Whishaw, 1982; Sutherland, Whishaw, & Kolb, 1983).

Briefly, the Morris water task is a spatial learning and

memory task that requires the subject to locate a fixed

hidden escape platform from various start positions

using environmental information external to the pool

(Morris, 1981). A significant amount of research has

accumulated to show that normal acquisition of thistask is dependent on the integrity of the hippocampus in

the rodent (Ferbinteanu et al., 1998; Morris et al., 1982;

Sutherland et al., 1982, 1983), and human versions of

this task are also sensitive to hippocampal dysfunction

in the human (Astur, Taylor, Mamelak, Philpott, &

Sutherland, 2002).

To test our hypothesis, rat dams consumed one of

three diets throughout gestation: a liquid diet containing5% ethanol, an isocalorically equivalent liquid diet, and

laboratory rat chow. Adult offspring from each of these

maternal conditions were trained on the standard, spa-

tial version of the water task developed by Morris

(1981). Surprisingly, the learning curves for the three

groups were virtually identical from the beginning of

training to asymptotic performance.

This pattern of behaviour on a learning and memorytask that is sensitive to hippocampal dysfunction was

paradoxical. One possible explanation for this lack of

effect was that the neurobiological changes in the hip-

pocampus found in the adult offspring of dams that

consumed ethanol (Sutherland et al., 1997), were not

sufficient to alter behaviour. Another intriguing possi-

bility was that tasks sensitive to hippocampal dysfunc-

tion might fall along a continuum of sensitivity to thissystem. This is supported by evidence showing that

relatively simple versions of spatial, context condition-

ing, and configural/relational tasks are not particularly

sensitive to hippocampal dysfunction, while versions of

the these tasks that place a higher demand upon these

cognitive systems are extremely sensitive (Frankland

et al., 1998; McDonald & White, 1995a, 1995b; Mc-

Donald et al., 1997). This work suggests that the logicaldescription of a task as spatial, contextual, or configu-

ral/relational is not sufficient to predict the necessity for

hippocampal function. For the current discussion, it

suggests that subtle alterations of the neurobiological

integrity of the hippocampus might go undetected using

tasks that place a low demand on hippocampal

processing.

To test this hypothesis, we used a version of theMorris water task that was developed to demonstrate

that the dorsal striatum and hippocampal learning and

memory systems could acquire information in parallel

and to demonstrate a competitive interaction between

these memory systems. Fig. 3 shows the training pro-

cedures for this version of the water task.

During acquisition, the visible platform is located at a

fixed location in the water maze on days 1–3, and on thefourth day the visible platform is replaced with a sub-

merged hidden platform. Consequently, animals acquire

both a cue response to the visible platform and also

learn to use extramaze distal cues to find the hidden

platform. The sequence of three visible platform days

followed by a hidden platform session is repeated thrice

for a total of 12 acquisition days (Sutherland & Rudy,

1988). On day 13, the visible platform is relocated in thequadrant diagonally opposite to the training goal loca-

tion (McDonald & White, 1994). Fig. 4 shows the two

possible response strategies animals can adopt on the

competition test. Starting from the point at the edge of

the pool that is equidistant to the �old� spatial locationand the visible platform currently repositioned in the

opposite quadrant, subjects may choose to swim directly

to the visible platform (a cue response; top panel) orvisit the former spatial location of the goal, which was

hidden on every 4th day of acquisition (a place response;

bottom panel).

Table 1 summarizes the results of a lesion study using

the combined cue-place task. Control subjects demon-

strated normal performance on visible and hidden

platform trials, however the group was split 50/50 on the

competition test with half of the animals swimmingmore-or-less directly to the visible platform (a cue re-

sponse) and half visiting the �old� spatial location (a

place response) before escaping to the visible platform

on the competition test. Subjects with hippocampal

Fig. 4. Depiction of the two types of responses made by individual

subjects during the competition test on the final day of cue-place

training. The top panel shows a cue response in which the subject

swims directly to the previously reinforced cued platform that is now

located in a new spatial location. The bottom panel shows a place

response in which the subject swims directly to the previously rein-

forced spatial location. Normal groups of rats split in the type of re-

sponse they make on this competition task with approximately half

using a cue response and the rest using a place response.

Table 1

Summary of the results reported by McDonald and White (1994)

Group Acquisition phase Competition test

Visible

trials

Hidden

trials

Cue

response

Place

response

Controls Normal Normal n ¼ 4 n ¼ 4

HPC lesion Normal Impaired n ¼ 8 n ¼ 2

DLS lesion Normal Normal n ¼ 2 n ¼ 7

Table 2

Summary of the results reported by Sutherland et al. (2000)

Group Acquisition phase Competition test

Visible

trials

Hidden

trials

Cue

response

Place

response

Controls Normal Normal n ¼ 7 n ¼ 5

Alcohol

pre-exposed

Normal Normal n ¼ 11 n ¼ 2

Pair-fed Normal Normal n ¼ 6 n ¼ 4


(HPC) damage demonstrated normal performance on

the visible platform days, impaired performance on

hidden platform days, and chose the visible platform (a

cue response) on the competition test. Subjects with

dorso-lateral striatum (DLS) lesions demonstrated nor-

mal performance during visible and hidden platform

trials but chose the previously reinforced spatial position

on the competition test. These results suggested that,among other things, perturbations of one learning and

memory system can enhance the ability of another

learning and memory system to control behaviour when

alternative response strategies are possible (McDonald

& White, 1994).

These results have important implications for the ef-

fects of moderate prenatal alcohol exposure on cognitive

function because it is possible that the functional effects ofthis developmental perturbation on the hippocampus

would be revealed in a test situation that places a higher

demand on hippocampal processing than the standard

version of the Morris water task. The competition test

places a high demand on hippocampal processing because

an intact dorsal striatal-based memory system competes

for behavioural control during the ultimate test. If the

hippocampus is compromised, the habit system will gain

control over behaviour. As can be seen in Table 2, the

results clearly showed that adult rats that were exposed to

moderate levels of alcohol during prenatal development

showed a strong preference (11/13) for swimming directly

to the visible platform during the competition test. Incontrast, approximately half of the normal rats and half

of the pair-fed rats preferred the visible platform.

This is the first demonstration, to our knowledge, of

an alteration in the balance between learning and mem-

ory systems caused by a prenatal developmental event.

The implications of this series of experiments should not

be underestimated because they show that complex

behavioural patterns in adulthood can be permanentlyaltered by a single prenatal event. Hence, these types of

events can fundamentally affect the overall organization

of memory in the mammalian nervous system and can

lead to abnormal behavioural patterns in adulthood.

1.4. Psychiatric disorders: The central role of interacting

memory systems

In the scientific literature there is an emerging focus

on the idea that the etiology of almost all major psy-

chiatric disorders are linked to abnormalities in brain

areas implicated in learning and memory processes. The

evidence suggests that dramatic changes in the rela-

tionship of these systems to one another, and with other

brain systems, lead to abnormal manifestations of be-

haviour. These cognitive and behavioural abnormalitiesinclude schizophrenia (Hanlon & Sutherland, 2000;

Lipska & Weinberger, 2002); anxiety (Hariri et al.,

2002); depression (McEwen, Magarinos, & Reagan,

2002; Santarelli et al., 2003; Sheline, Gado, & Kraemer,

2003); and drug abuse (Dickinson, Wood, & Smith,

2002; Everitt, Dickinson, & Robbins, 2001; White, 1996,

2002) among others.

Historically, theories about the etiology of these ma-jor psychiatric disorders have been dominated by single

factor theories. The idea was that these complex brain

disorders were caused by alterations in a neurotrans-

mitter system, gene or some other single factor. There are

many single factor theories of brain disorders that con-

Fig. 5. A hypothetical scenario in which GDE factors alter the orga-

nization of the brain in which prenatal alterations in the hippocampus

and amygdala alter their functions as well as affecting portions of the

prefrontal cortex. These changes in the organization of different

memory/behavioural systems and other brain regions results in the

manifestation of various symptoms associated with schizophrenia.


tinue to dominate important areas of research. Examplesof such theories include the idea that schizophrenia is

caused by an over-activation of the neurotransmitter

dopamine (Seeman, Guan, & Van Tol, 1993), or that

Alzheimer�s disease, in which alterations in a small

number of genes leads to over-expression of beta-amy-

loid peptide or neurofibrillary tangles, is associated with

neuronal damage and cognitive deficits (Pericak-Vance

& Haines, 1995). Although single factor theories havegenerated a significant amount of important research,

they do not accurately account for the complex etiologies

of these disorders (see Hanlon & Sutherland, 2000;

Lipska & Weinberger, 2002; McDonald, 2002).

In the final portion of this review we will discuss the

etiology of three classes of psychiatric disorders from the

interacting memory systems perspective (IMST). First,

the relationship between prenatal damage to the amyg-dala and hippocampus, prefrontal cortex activity, and

schizophrenia will be discussed. As well, the functional

implications of this neural damage and disconnection

syndrome are discussed. Second, the etiology of drug

abuse and the role of different learning and memory

systems are discussed. Finally, the role of various

learning and memory systems in mood disorders is

presented.

1.5. Schizophrenia

Recent work suggests that alterations in the prenatal

development of the hippocampus and/or amygdala may

be a critical event in the overall etiology of schizophre-

nia. The idea is that some possible combination of GDE

factors would alter the development of the hippocampusand/or amygdala and their functional relationships to

the rest of the brain. These changes would not be fully

revealed until early adulthood, and possibly be triggered

by experiences in adulthood (e.g., stress).

Several developmental rat models of schizophrenia

have been developed with significant predictive value

(Hanlon & Sutherland, 2000; Lipska & Weinberger,

2002). This work is based on the idea that the hippo-campus and/or the amygdala are damaged early during

brain development and that this event fundamentally

alters the organization of the brain in adulthood leading

to the myriad of symptoms associated with schizophre-

nia. For example, a neonatal lesion of the ventral hip-

pocampus in rodents produces many of the neural and

behavioural changes associated with schizophrenia in

humans. These changes include alterations in areas likethe nucleus accumbens and prefrontal cortex as well as

changes in the relationship of the hippocampus and

amygdala to these brain areas. Changes in the organi-

zation of these memory/behavioural systems and their

relationships with the nucleus accumbens and the pre-

frontal cortex are thought to underlie the emergence of

abnormalities in various dopamine-related behaviours

in adulthood. These abnormalities include enlargedventricles, increased action of postsynaptic dopamine

receptors, morphological changes in prefrontal cortex

and related deficits on tasks sensitive to prefrontal

function (Hanlon & Sutherland, 2000; Lipska & Wein-

berger, 2002).

Fig. 5 shows a hypothetical scenario in which GDE

factors resulted in altered relationships among various

memory/behavioural systems, and their relations withother neural systems. These alterations include hippo-

campal and amygdala dysfunction that will result in

relationship changes between these medial temporal

lobes structures and prefrontal cortex. These changes

would result in an increased dominance of the S–R habit

system by the dorso-lateral striatum as well as other

systems.

Taken together, these rodent models of schizophreniashow a strong relationship between early alterations in

medial temporal lobe affecting areas with direct ana-

tomical connections like the nucleus accumbens and the

prefrontal cortex. According to this work, the altera-

tions in dopamine related behaviour and prefrontal

function are a secondary consequence of prenatal al-

terations in learning and memory systems like the hip-

pocampus and amygdala.From the IMST view, early neonatal lesions of the

hippocampus and/or amygdala change the structure and

integrity of brain regions like the nucleus accumbens

and prefrontal cortex. The effect of this fundamental

change in the organization of the brain on behaviour

can best be understood by looking at the change in re-

lationships between various memory/behavioural sys-

tems, some of which have been altered and others thathave not. The idea is that certain patterns of interactions

would dominate thought and behavioural control in

normal subjects, and a different pattern of interactions

would occur in subjects with schizophrenia.


1.6. Drug abuse

Various theories of the neural mechanisms of drug

abuse have been put forward. One popular view is that

addicts administer drugs for their reward or pleasure-

inducing effects. This is sometimes referred to as the

hedonic theory of drug addiction. Essentially the idea is

that drug consumption results in the activation of do-

pamine cells in the ventral tegmental area which leads todopamine release in the nucleus accumbens and pre-

frontal cortex (Wise, 1996). It has been suggested that

increases in corticolimbic dopamine levels produce a

pleasurable experience (Volkow, Fowler, & Wang, 2002)

as well as affecting various cortical regions involved in

attentional processes and decision-making that could

affect various behaviours underlying addiction. A related

theory suggests that withdrawal from addictive drugsproduces reductions in dopamine release and action

leading to an anhedonic state that mediates relapse to

drugs. A third theory of addiction called the incentive

sensitization theory (Kelley & Berridge, 2002; Robinson

& Berridge, 1993) suggests that drug abuse is mediated

via mechanisms linking reward to drug associated stim-

uli, which in turn results in compulsive behaviours linked

to drug addiction. According to this view, corticolimbicdopamine release is critical for behaviours necessary for

obtaining rewards (Berridge & Robinson, 1998).

Another theory focuses on various learning and

memory systems in which the normal functions of these

complex neural circuits become subverted leading to

compulsive drug seeking behaviours (Everitt et al.,

2001). In this model, drugs of abuse initiate plasticity

mechanisms in different learning and memory systemsthat come to control behaviour of the individual over

other pre-existing memories. An earlier and slightly

different formulation of this view (White, 1996) suggests

that experience with addictive drugs are encoded and

stored like other experiences except that drugs of abuse

only mimic a subset of the action of natural reinforcers

in the brain. It is this differential reinforcement effect of

drugs combined with these actions on distinct learningand memory systems that produce addictive behaviours.

In this model, the amygdala acquires information that

promotes approach and interaction with drug associated

stimuli. The dorsal striatum promotes the acquisition of

stimulus–response (S–R) habits and the hippocampus

acquires information about the context in which drug

stimuli are obtained (White, 1996).

1.7. Drug abuse and interacting memory systems theory

The interacting memory systems theory (IMST) view

of the organization of memory/behavioural systems in

the mammalian brain might be a powerful way of un-

derstanding the neural basis of drug addiction. The

various theories mentioned above indicate the critical

role different learning and memory systems play in drugaddiction in which powerful plasticity processes and

associated memories are formed during drug experiences

that come to dominate behavioural control. White�s(1996) theory of drug addiction, in particular, is an in-

teresting fusion of multiple learning and memory sys-

tems theory and a novel reinforcement theory.

However, future work will need to emphasize the

dynamic and interactive nature of these systems andwhat role these interactions might play in addictive be-

haviours particularly when trying to develop treatment

regimes. The logic behind this claim is that it appears

that certain drugs of addiction modulate plasticity pro-

cesses in specific learning and memory systems but not

others (White, 1996), while another drug of abuse might

have a different pattern of influences. This suggests that

certain addictions might be heavily based on certainmemory/behavioural circuits while addictions to an-

other drug could be based on a different set of circuits,

or even a different subset of circuits. For example, drug

A might strongly enhance plasticity processes in dorsal

striatum that is thought to mediate stimulus–response

(S–R) habits (Packard et al., 1989) while drug B might

elicit addictive behaviours via enhancement of plasticity

processes in the hippocampus and amygdala thought tomediate contextual and stimulus–reward associations

(White & McDonald, 2002). If true, the treatments

necessary to deal with these subtypes of learning-based

addictions would require different approaches. One

approach would be to try and eliminate memories

mediating the abherrant behaviour. Alternatively, en-

hancement of other learning and memory systems not

mediating the addictive behaviours could be utilized todislodge the suspected system from behavioural control.

Another window on the mechanisms of drug addic-

tion that the IMST might open is an explanation for

individual differences in susceptibility to drug addiction

(Glantz & Pickens, 1992). We have previously argued

that although these learning and memory systems affect

behaviour, there are GDE factors that alter the rela-

tionships between these systems and the relationship ofthese systems to other brain areas. It is believed that

normal and abnormal manifestations of behaviour like

drug addiction are determined, to a large extent, by

some complex set of interactions between these factors

that can have a major effect on the organization of the

brain. Thus, interactions between GDE factors can af-

fect neurobiological integrity and impart an organiza-

tional change in the relationship of these memory/behavioural systems to one another, and with other

brain systems that could make an individual more sus-

ceptible to drug addiction.

One possible neural change that could mediate ad-

dictive behaviours is via enhanced behavioural control

exhibited by one memory/behavioural system. Fig. 6

shows a hypothetical scenario in which various GDE

Fig. 6. A hypothetical scenario in which GDE factors alter the orga-

nization of the brain in a way that makes this individual more sus-

ceptible to drug addiction to a particular substance. The

administration of this drug of abuse triggers a series of events that lead

to the dominance of the S–R habit system in controlling behaviour.

(The increase in size of the striatum object in this figure is designed to

indicate an increased influence over behaviour and not a literal in-

crease in size).


factors interact to enhance the dominance of the S–R

habit system that would lead to an increased tendency

towards habitual control over behaviour. This could be

influenced by the ease of access to common output sites(Ferbinteanu & McDonald, 2001; McDonald & White,

1995a, 1995b; White & McDonald, 1993) or via en-

hanced plasticity processes associated with cognitive

processes linked to addiction.

A second possibility is that, in particular individuals,

alterations in brain organization caused by GDE factors

can lead to a bigger reward signal occurring when drugs

of abuse are administered. This could result in an ac-celeration of specific types of learning and memory

processes associated with compulsive drug seeking.

Fig. 7. GDE factors interact to alter the organization of the brain in a

way that enhances reward signals when drugs of abuse are adminis-

tered. The reward signal is represented by an increase in dopamine

release in the ventral tegmental area/nucleus accumbens projection.

This signal preferentially enhances amygdale-based pavlovian learning

and memory processes that can influence addictive behaviours by an

individual�s tendency to approach and maintain contact with cues,

individuals, and situations associated with drug administration.

Fig. 7 shows a hypothetical scenario in which the GDEfactors alter the organization of the brain which results

in a more powerful reward signal to a particular drug

dose, possibly represented in the brain by an increase in

dopamine release in the VTA/nucleus accumbens

(Koob, 1992). This enhanced sensitivity of the meso-

limbic dopamine system to drugs of abuse could result in

an acceleration of learning and memory processes de-

pendent on these signals (Hiroi & White, 1991) and ul-timately behavioural control by these systems.

A final example is based on the idea that various

GDE factors could lead to an organizational change in

the brain resulting in a reduction of inhibitory control

via prefrontal cortical mechanisms (Kolb, 1990). Fig. 8

shows this reduction of prefrontal inhibitory control

which could result in increased behavioural control by

memory/behavioural systems that require the contribu-tion of executive systems for appropriate choice behav-

iours (Fuster, 1989; Moscovitch, 1994).

1.8. Mood disorders

The mood disorders include many of the most com-

mon psychiatric disorders found in the general popula-

tion including depression, anxiety disorder, andobsessive–compulsive disorder (OCD). Hypotheses

about the etiology of these disorders consistently suggest

that disruption of major neurotransmitter systems are at

the root of these brain dysfunctions. Once again, our

view is that these alterations in neurotransmitter systems

might be the secondary consequences of alterations to

key memory/behavioural systems including the hippo-

campus, amygdala, dorsal striatum, and the prefrontalcortex. These mood disorders are now being linked to

permanent structural and biochemical changes in these

brain structures.


way that reduces prefrontal cortex inhibitory control of memory/

behavioural systems like the amygdala and striatum that results in

increased behavioural control by memory systems that require the

contribution of executive systems for appropriate choice behaviour in

highly rewarding but personally detrimental behavioural patterns.


Depression is characterized by recurrent episodes ofdecreased energy, appetite, attention, and negative

mood states (Cassens, Wolfe, & Zola, 1990). Alterations

in the neurotransmitter serotonin are thought to be the

main cause of depressive episodes and the administra-

tion of drugs that enhance serotonergic levels have had

considerable success in treating depression.

A different view of the etiology and mechanisms of

depression has emerged recently that links damage to thehippocampus to this disorder (Sapolsky, 2000). Further-

more, a down-regulation of neurogenesis in the adult

hippocampus has also been linked to depression and se-

rotonergic medications commonly used to treat depres-

sion up-regulate neurogenesis in hippocampus (Malberg,

Eisch, Nestler, & Duman, 2000; McEwen et al., 2002).

Alterations in the functions of the amygdala have also

been consistently reported in depressive patients (Shelineet al., 2003) in whom the amygdala becomes overactive

when responding to negative experiences.

From the IMST view these seemingly unrelated

changes to the hippocampus and amygdala might not be

unrelated after all. It is possible that the GDE factors

might lead to elevated glucocorticoid levels. If these

levels are chronically elevated they can lead to hippo-

campal cell death (Sapolsky, Krey, & McEwen, 1985)and neurogenesis down-regulation (Lemaire, Koehl, Le

Moal, & Abrous, 2000). Any event that leads to a

dampening of hippocampal function could result in in-

creased dominance of other memory/behavioural sys-

tems (White and McDonald, 2002). Thus a secondary

consequence of dampening hippocampal function would

be to increase dominance of amygdala influence on

thoughts and related behaviour (McDonald & White,1995a, 1995b; Sheline et al., 2003; White & McDonald,

1993). This increased amygdala influence might lead to

increases in the negative affect attached to a wider range

of situations or events. Fig. 9 shows a hypothetical


way that results in symptoms and behavioural patterns associated with

clinical depression. Atrophy of hippocampus, anatomically and func-

tionally, and enhancement of right amygdala dominance over thought

and behaviour results in negative mood states and associated changes

in behaviour.

scenario in which, because of some complex interactionsbetween various GDE factors, an individual suffers from

depression. The depiction shows a shrinkage of the

hippocampus, anatomically and functionally, and an

enhancement of the right amygdala dominance of

thought and behaviour. The right amygdala in humans

is thought to be specialized for influencing negative

emotions.

Anxiety disorders are associated with inappropriatelevels of fear and related physiological and behavioural

concomitants warranted by the situation or event. It is

thought that disruptions of the GABAergic neuro-

transmitter system are central to the etiology of anxiety

disorders and the widespread treatment success of the

benzodiazepine drugs supports this view (Rickels &

Schweizer, 1987).

Various memory/behavioural systems, particularlythe hippocampus and amygdala, are thought to allow

individuals the ability to confine and constrain their

fearful responses to the original event. Anxiety disor-

ders might result from a weakening of these systems

resulting in a generalization of fear to unrelated cues

and situations. Thus, a subject with an anxiety disorder

is thought to be unable to differentiate between cues,

environments, or episodes that are associated with fearand those that are not. Many researchers have con-

cluded that anxiety disorders must be linked with

changes in the hippocampus and/or amygdala (Amaral,

2003; Hariri et al., 2002; Ledoux & Muller, 1997;

Quirk & Gehlert, 2003; Walker, Toufexis, & Davis,

2003), and it is possible that these changes occur be-

cause of some interaction between the GDE factors.

Fig. 10 shows a hypothetical scenario in which, because


way that results in symptoms and behavioural patterns associated with

general anxiety disorder. Changes in the hippocampus and amygdala

and/or their relationship with one another resulting in general anxiety

by decreasing their influence on brainstem and hypothalamic neural

systems that produce the physiological responses associated with fear

and anxiety. These responses would include increased heart rate, res-

piration, hormone release, ascending neurotransmitter release, and

avoidance behaviours.


of some complex interactions between the GDE fac-tors, an individual suffers from anxiety. In this indi-

vidual, changes in the hippocampus and amygdala and/

or their relationship with one another and other brain

regions like the brainstem and hypothalamus would

result in general anxiety. A loss of amygdala and hip-

pocampal control over brainstem and hypothalamic

regions that mediate the physiological responses asso-

ciated with fear and anxiety would increase general-ization of fear to unrelated situations.

Obsessive–compulsive disorder (OCD) is another

class of mood disorder that is characterized by reoc-

curring obsessions and/or compulsions that disrupt

normal daily functions of the individual (DSM-IV).

Obsessions are defined as incessant, intrusive thoughts

or impulses. Compulsions are repetitive response pat-

terns that are thought to occur in response to variousobsessions. Any attempt by the individual suffering from

OCD to resist these compulsive behaviours results in

high anxiety.

From the IMST view, OCD might be caused by an

alteration in the relationships between the dorso-lateral

striatum, prefrontal cortex, and the amygdala/hippo-

campus axis. These changes in the organization of these

different memory/behavioural systems would be causedby interactions with the GDE factors. Dysfunction of

the amygdala/hippocampus would result in heightened

anxiety levels. A dampening of prefrontal cortex func-

tion would lead to a reduction in inhibitory control over

thoughts and behaviour. A secondary consequence of

dysfunction in these areas would be an increased dom-

inance of the dorso-lateral striatum S–R habit system

that would elicit inappropriate repetitive response pat-terns (compulsions).

Recent evidence supports this complex view of OCD

and implicates changes in the dorsal striatum, pre-

frontal cortex and the amygdala/hippocampus axis

(Harris & Dinn, 2003; Hoehn-Saric & Greenberg, 1997;

Kim et al., 2003; Konig et al., 1998; Kuelz, Hohagen,

& Voderholzer, 2004; Kwon et al., 2003; Szeszko et al.,

2004).

2. Conclusions

This current review and analysis puts forth the idea

that the organization of memory in the mammalian

brain and the neural systems that mediate them must

play a pivotal role in our thoughts, emotions, choices,actions, and even our personalities. According to this

view, complex interactions between neural circuits that

contain remnants of an individual�s past experience not

only provide the basis of your identity but also exert an

enormous influence over ongoing behaviour. Interac-

tions between these systems and related brain areas are

thought to determine who we are and how we behave in

particular situations. An extension of this idea is thatabnormal manifestations of behaviour are caused, to a

large extent, by alterations in the relationships among

different memory/behavioural systems and other brain

areas.

Symptoms associated with various psychiatric

disorders are hypothesized to be caused by complex

interactions between a patient�s genetic background,

their pre- and post-natal development, and their lifeexperiences. All of these factors can have major effects

on the organization of the brain and even subtle alter-

ations could affect the overall relationship between

memory/behavioural systems (balance) as well as the

relationships among memory/behavioural systems and

the rest of the brain. In many instances, it is this rela-

tionship between GDE factors and interactive memory

systems which ultimately determines manifestations ofnormal and abnormal behaviour.

In summary, evidence was provided showing a com-

petitive interaction between two memory/behavioural

systems and how a simple pre-natal developmental event

affected the nature of this interaction (McDonald &

White, 1994; Sutherland et al., 2000). It is important to

note that although the above example shows an effect of

a developmental factor on a competitive interactionbetween the dorsal striatum and hippocampus, it is hy-

pothesized that synergistic interactions can be affected in

this way as well that could lead to changes in thought

processes and behavioural patterns. A review and

analysis of research showing a central role of memory/

behavioural system dysfunction and various psychiatric

disorders was also presented. One idea that emerged

from this analysis is that it is important to understandthe primary and secondary consequences of memory/

behavioural system dysfunction. That is, the symptoms

of a particular psychiatric disorder are most likely

mediated by changes among memory/behavioural sys-

tems during development and secondary changes that

affect neurobiological processes later in life. As a result,

some adult processes are altered while others are left

intact, and may come to dominate thought and behav-iour in the presence of down-regulated or compromised

neurobiological processes.

One interesting point that emerges from the current

analysis is that many of these seemingly disparate dis-

orders affect similar neural circuits (e.g., OCD and

schizophrenia). A corollary that may follow from these

demonstrations is that the temporal aspects of brain

damage could influence different disorders. For exam-ple, schizophrenia appears to be caused by early devel-

opmental alterations whereas OCD damage may occur

later, possibly post-natal. Another possibility is the

overall extent of damage or the pattern of damage

within each system is different. For example the dorsal

striatum can be anatomically and functionally subdi-

vided into at least two systems (McGeorge & Faull,


1989). In a complex disorder like OCD, a unique patternof damage to portions of each of these areas might be

responsible for the psychological and behavioural effects

of the brain dysfunction. Future work will be required

to assess these ideas.

In closing, emerging evidence from a wide range of

empirical studies suggest that learning and memory

systems are at the core of many neurodegenerative and

psychiatric disorders. Detailed information about thefunctions of these various brain systems and the inter-

actions between them, using both basic and applied re-

search approaches, is critical for future treatment and

prevention of these debilitating disorders.

Acknowledgment

Dr. Robert McDonald is currently a Canada Re-

search Chair.

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multiple memory systems: the power of interactions

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